US3093636A - Intermediates in the conversion of 11alpha-hydroxy-diosgenin to cortisone - Google Patents

Description

United States Patent .INTERMEDI A'IES IN THE CONVERSION OF 11a- HYDROXY-DIOSGENIN TO CORTISONE Carl Djerassi, Otto Halpern, and Octavio Mancera, Mexico City, Mexico, assignors, by mesne assignments, to Syntex Corporation, a corporation of Panama No Drawing. Filed Oct. 3, 1958, Ser. No. 765,056 Claims priority, application Mexico Oct. 4, 1957 22 Claims. (Cl. 260239.55)

The present invention relates to cyclopentanophenanthrene compounds and to a novel process relating thereto. More particularly, the present invention relates to a novel process for the production of cortisone, or other cortical hormones which may be derived therefrom, startwith lla-hydroxy diosgenin and to ,certainnbvel intermediates.

In U.S. Patent No. 2,776,969, granted January '8, 1957, there is disclosed and claimed lla-hydroxy-diosgenin (A -22-isospirostcn-3p-llu diol) aswell as certain esters thereof and a method for the preparation thereof.

In accordance with the present invention we have discovered that lla-hydroxy-diosgenin may be converted The compound thus formed is then reesteri-fied at C-3.

As previously set forth, the l6u,l7a-oxido compound and its esters just referred to are the key intermediates for the remainder of the present novel process which involves the further steps of bromination both to protect the 5,6 double bond and in position 21 (in one modification bromination at 0-12 is also produced), reaction of HBr with the oxide group at 16,17 to prepare the 170:- hydroxy-16- bromo compounds, sulbstitution of the 21-bromo by iodine and subsequently by acetate, oxidation of the B-hydroxy group to a 3-keto group, reconstitution of the 5,6-doub1e bond and removal of bromo groups from C16 and 0-12.

That portion of the process of the present invention involving the production of esters of 16a,l7oc- OXid0- A pre-gnen-3fi-ol-1L20dione is illustrated by the rfol lowmg equation:

into cortisone by a process involving as a first step the. a.

3,093,636 Patented June 11, 1963 In the above equation R represents an ester group of a hydrocarbon carboxylic acid of less than 12 carbon atoms. These may be those conventional in the art i.e. aliphatic, cyclic or mixed cyclic-aliphatic. In general however, for the process the lower fatty acid esters are desirably used such' as acetate or propionate and may desirably represent these acyl groups. I

In practicing the steps above set forth the hydroxyl oxidative degradation group at C3 of lla-hydroxy diosgenin was selectively esterified by treating the free compound with slightly over one molar equivalent of a lower fatty acid anhydride such as acetic anhydride in pyridine solution and at a temperature substantially below room temperature. The 3-mono lower fatty acid esters of lla-hydroxy-diosgenin gthus prepared, were then oxidized by an oxidizing agent for secondary hydroxyl groups, chromium trioxide in aqueous acetic acid solution, forexample to form ll-ketodiosgenin lower fatty acid esters. Oxidative degradation of the sapogenin side chain by the usual methods i.e.

heating under pressure with a lower fatty acid anhydride (preferably acetic) and treatment with chromium trioxide in acetic acid etc. gave the 3-lower fatty acid esters of A -pregnadien-3B-ol-l1,2O-dione. The 16-,17-double bond of these compounds were then epoxidized preferably with hydrogen peroxide in alkaline solution (i.e.

alkali metal hydroxide) to give 16u,17oc-oxido-A -pregneously saponified. Conventional esterification with lower fatty acid anhydrides then gave the corresponding 3- lower fattyacid esters ofthis oxido compound.

The compounds just described are inter-mediates tor the production of cortisone by further process steps illustrated by the following equation:

of Q

I bromination l R and then HBr R0 2 Br l bromination and hydrolysis CHzOAC (llHzBl I O 100 "-"O OH 0- 0 Tm sodium iodide and KAe H0 Br l bromination,

oxidation and zinc CHQOAO CHzOAc to a "-"O I o l rearrangement O i l HBr onioae onioxc oir it LU Q In the above equation 'R represents the same ester groups as heretofore set forth and Ac represents acetate.

At indicated in the above equation, the 3-esters, preferably lower fatty acid ester, of 16a,17oz-O)ddO-A -pregnen-Sfi-ol-ILZO-dione are first brominated with bromine preferably in carbon tetrachloride to form the corresponding 5,6-dibromo compound i.e. the lower fattye acid esters of 5,6-di'bromo-16ot,17a-oxido-pregnan-35-ol-1 l,20-dione. These compounds may be isolated conventionally or the reaction solution containing them treated directly with hydrogen bromide in glacial acetic acid to form the corresponding 3-lower fatty acid esters of 5,6,16/8-tribromopregnan-3B,17a-diol-11,20-dione. Here again these intermediates may be recovered or the solution treated again with one more molar equivalent of bromine to form the corresponding 3-lower fatty acid esters of $6,165,21- tetrabromo-pregnan-Sfi,17u-diol-11,20-dione. The 3-ester Raney (rr nickel group of these compounds was then hydrolyzed with acid, such as dry hydrogen chloride in a lower aliphatic )1 alcohol such as methanol, to give the free tetrabromo compound indicated in the equation.

Treatment of the free tetrabromo compound with sodium iodide in methanol or other lower aliphatic alcohol gave the corresponding 21-iodo compound with the 5,6-double bond reconstituted i.e. 16fl-bromo-21-iodo-A pregnen-3 3,17a-diol-11,20-dione. This compound when treated with potassium acetate gave the 2l-acetate of 16oz, 17a-oXido-A -pregnen-3BJl-diol-l 1,20-dione. Treatment of this oxido compound in methylene chloride with bromine at a temperature below room temperature gave the corresponding 5,6-dibromo compound which was then oxidized to the corresponding 3-ketone to thus prepare (after removal of the 5,6-dibrorno groups with zinc) the 21-acetate of 16a,17u-oxido-A -pregnen-2Pol-3,11,20-trione. Treatment with strong mineral acid such as hydrochloric acid rearranged the A -double bond to the A -double bond as indicated. Finally reaction of the t,17doxide group with hydrogen bromide and exchange of the 16,8-bromo for hydrogen by means of Raney nickel gave cortisone acetate.

Another modification of the process of the present invention starting with the same oxido compound and involving the production of intermediate 12-bromo compounds is illustrated in the following equation:

CHzBr O on lHBr HBr and Raney nickel ho H O l Raney WV added in the course of half an hour.

CHzOAC CH OAO In the above equation R and Ac represent the same groups as heretofore.

As indicated above the modification illustrated differs from that previously described in that the double bond of the starting material is first brominated,then treated with HBr and then again treated with bromine to form the 3-lower fatty acid esters of 5,6,12,16fl,21-pentabromopregnan-3/3,17a-diol-.11,20-dione. These esters are then hydrolyzed to the free compound and this treated with sodium iodide to form 12,1GB-dibromo-Zl-iodo-M-pregnen-3,3,17a-diol-11,20-dione. Treatment of this last compound with potassium acetate gave the 2l-acetate of 12- bromo 4611,17 oxido A pregnen 35,21 diol-ll, 20-d-ione. This compound was treated with bromine to give the corresponding 5,6,12-tribromo compound which was then oxidized to the 2l-acetate of 5,6,12-tribromo 1-6a,17a oxido pregnan 21 ol 3,11,20- trione. From this compound, as indicated in the equation, the bromine could either be completely removed with zinc or partially removed with sodium iodide, followed by rearrangement as previously described to the corresponding M-compounds'. In any event the resulting 3-k6t0-A -16m17ot-0Xld0 compounds are treated in the same way by opening the epoxide with hydrogen bromide and treatment with Raney nickel to remove either bromine at C-16 or both at C-l6 and C12.'

The following specific examples serve to illustrate but are not intended to limit the present invention.

Example I A solution of 50 g. of A -22a,25D-spirosten-3fl,1ludiol (lla-hydroxyrdiosgenin) in 200 cc. of pyridine was cooled to 0 C. and slowly treated, with stirring with tography.

45 g. of the crude lla-hydroxy-diosgenin 3-acetate was dissolved in 5 00 cc. of 90% acetic acid and then slowly treated under stirring with a solution of g. of chromium trioxide in 50 cc. of 80% acetic acid, which was The mixture was kept for 2 hours at room temperature, poured into ice water and extracted with ethyl acetate; the extract was washed with 5% sodium carbonate solution and water,

. dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was chromatographed on activated alumina and the crystalline fractions eluted were recrystallized from methanol. There was thus obtained 35 acetoxy A 22a,25D spirosten ll-one,

: acetic anhydride was heated for 8 hours in a pressure a temperature.

tate was collected, washed with water, dried and recrysbomb at 175-180" C. The mixture was poured into water and extracted with ether, and the extract was washed with water, dried over anhydrous sodium sulfate,

filtered and evaporated to dryness. The residual oil was dissolved in 400 cc. of acetic acid and 420 cc. of ethylene dichloride, cooled to 15 C. and treated dropwise with a solution of 27 g. of chromium trioxide in 460 cc. of acetic acid, with stirring and maintaining the temperature of the mixture below 15 C. After 2 hours at room temperature it was poured into water, extracted with chloroform, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was chromatographed in a column of unwashed alumina, thus producing A -pregnadien-3fi-ol-11,20-ditallization from methanol.

10 g. of the crude 16a,l7a-Qxido-A -pregnen-3 8-01-11, 20-dione was dissolved in 50 cc. of pyridine, mixed with 10 cc. of acetic anhydride and kept overnight at room After pouring into ice water the precipitallized from methanol, to yield 16u,l7cc-0Xid0-A -prgnen-3fl-ol-11,20-dione acetate.

A solution of 10 g. of 16m,17d-oxido-A -pregnen-3flol-11,20-dione acetate in a mixture of cc. of acetic acid and 100 cc. of carbon tetrachloride was cooled to 18 C. and treated with a solution of 4.2 g. of bromine in 30 cc; of carbon tetrachloride.

There was thus formed 'a' solution of 5,6-dibromo-16a,17a-oxido-pregnen-3fl-ol- 11,20-dione acetate. In another experiment this compound was isolated by concentrating the solution to dryness under reduced pressure and recrystallizing the residue from methanol.

The solution of 5,6-dibromo-l6a,l7a-oxido-pregnen- 3fl-ol-11,20-dione acetate, obtained as described above,

,was treated with 15 cc. of 32% solution of hydrogen bromide in glacial acetic acid, whereupon a solution of 5,6,16B-tribromo-pregnan-3B,17u-dio1-l1,20-dione acetate was formed. In another experiment the solution was concentrated under reduced pressure and the bromohydrin was isolated by crystallization of the residue from methanol.

. and then the carbon tetrachloride was removed under reduced pressure, avoiding overheating. The resulting suspension was poured into water and the precipitate formed was collected, washed with water and dried at 50 C. There was thus obtained the crude 5,6,l6/3,2l-tetrabromopregnan-3B,17a-diol-11,20 dione 3-acetate. The analytical sample was obtained by recrystallization from methanol.

3 g. of the crude 5,6,l65,2l-tetrabromo-pregnan-3fl, 17a-diol-11,20-dione 3-acetate was covered with 100 cc. of methanol and a slow stream of dry hydrogen chloride was introduced into the mixture, with stirring and maintaining the temperature around 30 C. When the hydrolysis of the acetoxyl group was complete the'color of the solution turned pale red and the stirring was con- "r' tinued for 45 minutes further. The mixture was diluted with water and the precipitate was filtered, washed with water and dried in vacuo, thus yielding the crude 5,6, l6 8,21-tetrabromo-pregnan-3,8,17u-diol-l1,20-dione. The

analytical sample was obtained by recrystallization from methanol.

The above crude 5,6,16,8,2l-tetrabromo-pregnan-Brfi, l7a-diol-11,20-dione was dissolved in 200 cc. of methanol, mixed with 34 g. of sodium iodide, stirred for minutes and then kept standing overnight. After diluting with water the iodination product was extracted with methylene chloride and the extract was washed with 3% sodium thiosulfate solution until decoloration, then with water and evaporated under reduced pressure, avoiding overheating. There was thus obtained l6 8-bromo-2l-iodo- A -pregnen-3B,17a-diol-l1,20-dione in crude form. The analytical sample was obtained by recrystallization from acetone-methanol at low temperature.

The crude 1618-brorno-21-iodo-A -pregnen-3B,l7a-diol- 11,20-dione was dissolved in 300 cc. of acetone, treated with 40 g. of recently fused potassium acetate and the mixture was refluxed for 4 hours. It was then concentrated to a small volume, diluted with water and extracted with ether. The extract was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to a small volume. Upon cooling there crystallized 16cc, 17a-oxid0-A -pregnen-3B,2l-diol-l1,20-dione 21 acetate. The analytical sample was obtained by recrystallization from acetone.

g. of 16a,17a-oxido-A -pregnen-3 8,2l-diol-l1,20-dione 21-acetate was dissolved in 50 cc. of methylene chloride, cooled to 10 C. and treated under stirring with 4.2 g. of bromine dissolved in 12 cc. of methylene chloride, in the course of 20 minutes and maintaining the temperature below 15 C. There was thus obtained a solution 5,6 dibromo-ltia,l7a-oxido-pregnan-3fl,2l-diol- 11,20-dione 21-acetate which was used for the next stage without isolation of the pure compound. The latter was obtained in another experiment by concentration of the methylene chloride solution under reduced pressure followed by crystallization of the residue from acetone.

To the solution of 5,6-dibromo-16a,17u-oxido-pregnan- 3fl,21-diol-11,20-dione 2l-acetate, obtained as described above, there was added 100 cc. of 90% acetic acid and then 4 g. of chromium trioxide dissolved in 10 cc. of water, with stirring, in the course of half an hour and maintaining the temperature of the mixture below 25 C. It was then stirred for 1 hour further at room tempera ture, diluted with water and 200 cc. of methylene chloride and the aqueous phase was re-extracted with methylene chloride. The combined organic solution was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. There was thus produced 5,6-dlbl0m0-160a,].70c-OXidO- pregnan-2l-ol-3,l1,20-trione acetate in crude form. The analytical sample was obtained by recrystallization from acetone-hexane.

10 g. of crude 5,6-dibromo-16u,l7a-oxido-pregnan-21- ol-3,11,20-trione acetate was dissolved in 100 cc. of methanol and then under stirring mixed with 4 g. of zinc dust, while the temperature was kept below 40 C. The stirring was continued for half an hour further and the supernatant solution was decanted and filtered. There was thus obtained a clear solution of 16a,17a-oxido-A -pregnen-2l-ol-3,11,20-trione acetate. In another experiment the compound was isolated by pouring the solution into water, extracting with ether, washing with water, evaporating to dryness and recrystallizing the residue from acetone-hexane.

The solution of 16a,17u-oxido-A -pregnen-21-01-3,ll, 20-trione ZI-acetate, obtained as described above, was

, treated with 3 cc. of concentrated hydrochloric acid and stirred at room temperature for 10 minutes. After diluting with water, the product was extracted with methylene chloride, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Crystallization of the residue from acetone-hexane yielded 16a,17aox-ido-A -preguen-2l-ol-3,l 1,20-trione 2 l-acetate.

To a solution of 5 g. of 16a,l7u-oxido-A -pregnen-2lol-3,ll,20-trione acetate in 40 cc. of glacial acetic acid there was added 30 cc. of a 30% solution of hydrogen bromide in glacial acetic acid, under continuous stirring. The color of the solution quickly changed and the bromohydrin, namely 16B-bromo-A -pregnen-l7a,2l-diol-3,ll, 20-tn'one acetate, started to precipitate. 'I he stirring was continued at room temperature for half an hour and the mixture was then diluted with water. The precipitate was collected by filtration and washed with water. The analytical sample was obtained by recrystallization from acetone-hexane.

5 g. of the still moist crude-bromohydrin obtained above was added to a suspension of 7.5 g. of Raney nickel in 150 cc. of methanol and the mixture was refluxed for 2 hours. The catalyst was removed by filtration under nitrogen and the filtrate was concentrated until precipitation. The precipitate was filtered from the cooled mixture, washed with water, dried and recrystallized from acetone-hexane, thus furnishing cortisone 21-acetate which was identical with an authentic sample of the product.

Example II In another experiment, 10 g. of A -pregnadien-3B- ol-11,20-dione acetate in mixture with 75 cc. of chloroform and 1 1t. of methanol was treated with 40 cc. of 30% hydrogen peroxide followed by 20 cc. of 5 N sodium hydroxide solution, at temperatures around room temperature, and the mixture was stirred for 16 hours; it was then acidified with acetic acid and the resulting 16:1, 17a-oxido-A -pregnen-3B-ol-l1,20-dione was isolated by extraction with chloroform.

Example III In another experiment 16a,17a-oxido-A -pregnen-3 8-ol- 11,20-dione acetate in methylene chloride solution was treated with one molar equivalent of bromine to produce a solution of 5,6-dibromo-l6a,l7or-oxido-pregnan-3fi-ol- 11,20-dione acetate in methylene chloride. This solution was then treated with hydrogen bromide in acetic acid and the resulting solution of 5,6,16/3-tribromo-pregnan-3fl, 17a-diol-11,20-dione fi -acetate was treated with another molar equivalent of bromine dissolved in methylene chloride. By addition of water and subsequent extraction with methylene chloride and concentration under reduced pressure, there was obtained 5,6,163,21-tetrabromo-pregnan-318,17a-diol-11,20-dione S-acetate, identical with the product obtained in accordance with Example I.

Example I V A solution of 10 g. of 16a,17a-oxido-A -pregnen-3fl-ol- 11,20-dione acetate in 200 cc. of methylene chloride was treated with 4.2 g. of bromine dissolved in 30 cc. of methylene chloride and with 15 cc. of glacial acetic acid containing 5 g. of dry hydrogen bromide, at room temperature. The solution was then heated to 40 C. and treated with 8.4 g. of bromine dissolved in 60 cc. of methylene chloride, which was added in small portions and waiting until decoloration before each addition and under stirring. The mixture was stirred at 40 C. for 20 minutes further, the methylene chloride was removed by distillation under reduced pressure, avoiding overheating, and the suspension obtained was poured into ice water. The precipitate was filtered, washed with water and dried in vacuo. There was thus obtained the crude 5,6,12,165, 21-pentabromo-pregnan-3/3,17a-diol-1 1,20-dione 3-acetate. The pure compound was isolated in another experiment after recrystallization from methanol.

The crude 5,6,12,16/3,21-pentabromo-pregnan-3 8,17adiol-11,20-dione B-acetate was mixed with 100 cc. of methanol and a slow stream of dry hydrogen chloride was introduced into the solution for minutes and keeping the temperature around 30 C. After diluting with water methylene chloride, washed with 3% sodium thiosulfate solution until decoloration and with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure in a bath kept at a temperature below 35 C. There was thus obtained 12,1618- dibromo 21 iodo-M-pregnenG/B,17u-diol-11,20-dione in crude form. The analytical sample was prepared by recrystallization from acetone-methanol at low temperature.

The crude 12,16;8-dibromo-21-iodo-A -pregnen-3B,.l7adiol-11,20-dione' was dissolved'in 300 cc. of acetone, mixed with 40 g. of recently fused potassium acetate .and refluxed for 4 hours. 'The mixture was concentrated to a small volume, diluted with water and extracted with ether. The extract was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to a small volume. Upon cooling there crystallized 12-bromo- 16a,17a-oxido-A -pregnen-35,2l-diol-l1,20-dione 21-ace tate. The analytical sample was obtained by crystallization from acetone.

10 g. of the 12-bromo-16a,17a-oxido-A -pregnen-3p, 21-diol-ll,20-dione 21-acetate was dissolved in 50 cc. of methylene chloride, cooled to 1 C. and treated with 4 g. of bromine dissolved in 10 cc. of methylene chloride, with stirring and keeping the temperature below 15 C., in the course of 20 minutes. There was thus obtained a solution of 5,6,IZ-tIibI'OmO-l6oc,17ct-0XidO- pregnan-3fi,21-diol-11,20-dione 21-acetate which was used for the next stage without isolation of the pure compound. The latter was obtained in another experiment by concentration of the methylene chloride solution under reduced pressure and recrystallization of the residue from acetone.

To the above solution of 5,6,12-tribromo-l6a,17u-oxidopregnan-3p,21-diol-11,20-dione ZI-acetate there was added 100 cc. of 90% acetic acid and then 3.8 g. of chromium trioxide in 10 cc. of water in the course of half an hour, with stirring and keeping the temperature :below 25 C. The mixture was stirred for 1 hour further at room temperature, diluted with Water and 200 cc. of methylene chloride and the organic phase was separated. The aqueous layer was re-extracted with methylene chloride and the combined methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under-reduced pressure. There was thus obtained the crude 5,6,l2-tribromo- 16a,17a-oxido-pregnan-21-ol-3,11,20-trione acetate. The analytical sample was obtained by recrystallization from acetone-hexane.

10 g. of the crude 5,6,IZ-tribromo-16u,17u-oxido-pregnan-21-ol-3,1l,20-trione acetate was dissolved in 200 cc. of methanol, mixed with 40 g. of sodium iodide and then the reaction product was worked up as described above for the reaction of 5,6,12,165,21-pentabromo-3fi, 17owdi0l-1L20-dl0n6 with sodium iodide. The pure substance was obtained by recrystallization from acetonehexane. The crude 12 bromo-l6a,l7a-oxido A -pregnen- 2.1-ol-3,1l,2=0-trione acetate was mixed with 1-00 cc. of methanol followed by 3 cc. of concentrated hydrochloric acid and the mixture was stirred at room temperature for minutes. After diluting with water the product was extracted with methylene chloride, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue crystallized from acetonehexane to furnish 12-bromo-16u,l7a-oxido-A -pregnen- 21-01-3, l 1,20-trione acetate.

To a solution of 5 g. of 12 -bromo-16a,l7a-oxido-A pregnen-21-ol-3,l1,20 trione acetate in cc. of glacial acetic acid there was added 2 cc. of a 30% solution of hydrogen bromide in acetic acid, dropwise and under mechanical stirring. The color of the reaction mixture quickly changed and the bromohydrin started to precipitate. The stirring'was continued at room temperature for half an hour and the mixture was then diluted with water, cooled and the precipitate was filtered and washed with water; there was thus obtained 12,16/3-di'bromo-A pregnen-l7u,2l-diol-3,11,20-trione 2l-acetate in crude form which without drying was used for the next stage. The analytical sample was obtained by recrystallization from acetone-hexane. V

5. g. of the above crude wet bromohydrin was added to .a suspension of '15 'g. of Raney nickel in 200 cc. of methanol and the mixture was refluxed for.4 hours and filtered under nitrogen; the filtrate was concentrated until an abundant precipitate separated and cooled. The precipitate was filtered, washed with water, dried and recrystallized from acetone-hexane, thus giving cortisone ,21acetate, identical with an authentic sample of the compound.

. Example'V' 5 g. of the crude 5,6,12-tribromo 16a,l7a-oxido-pregnan-21-ol-3,11,20-trione acetate, obtained as described in Example IV, was mixed with 50 cc. of methanol and 3 g. of zinc dust which was added in small portions, with stirring and maintaining the temperature below 40 C. The mixture was stirred for 1 hour further and then filtered, washing the filter with methanol. The combined filtrate and washings aiforded a solution of 16a,17a-oxido- A -pregnen-21-ol-|3,l1,20-trione acetate; in another ex periment the pure compound was isolated by addition of water, filtration of the precipitate and crystallization from acetone-hexane.

By treatment with hydrochloric acid the double bond of l6u,17ot-oxido-A -pregnen-2l-ol-3,l1,20-trione was rearranged to the A position, then formed its bromohydrin and finally substituted the bromine atom of the latter for a hydrogen atom, thus yielding cortisone 21-acetate, identical with the final compound of Example 1V. These reactions are similar to those of the transformation of 12-bromo-16a,l7a-oxido-d pregnen-2-1-ol-3,11,20 trione acetate into cortisone ZI-acetate described in Example IV.

We claim:

1. A process for the production of the lower fatty acid esters of 16a,17a-oxido-A -pregnen-33-01-11,20-dione comprising selectively acylating lla-hydroxy-diosgenin in an inert solvent at low temperature to form the 3-lower fatty acid esters thereof, oxidizing the esters with an oxidizing agent to form the 3-lower fatty acid esters of ll-keto-diosgenin, oxidatively degrading the side chain of the last mentioned esters to form the corresponding 3-lower fatty acid esters of A -pregnadien-3B-ol-11,20- dione, epoxidizing the last mentioned compound with a peroxidizing agent to form 1-6a,17a-oxido-A -pregnen-3/3- ol-ll1,20-dione and esterifying this last mentioned compound with a lower fatty acid anhydride.

2. The process of claim 1 wherein the oxidizing agent is chromium trioxide in acetic acid and the peroxidizing agent is hydrogen peroxide in the presence of an alkali metal hydroxide.

3. A process for the production of cortisone acetate comprising reacting -16a,17a-oxido-A -pregnen-3/3-ol-l1, 20-dione acetate with bromine and HBr to form a 5,6, 1649,21-tetrabromo-17a-hydroxy derivative thereof, reacting the tetrabromo derivative with sodium iodide and with potassium acetate to form a 2-1-acetate and remove the 5,6 and 16B bromo groups and reconstitute the 16u,l7a-oxido group, oxidizing the S-hydroxy group to a 3-keto group, again reacting the compound thus formed with HBr to form a l6fi-bromol7a-hydroxy compound and removing the lfi-bromo group.

4. The process of claim 3 wherein the tetralbromo derivative is further substituted with bromine at 0-12.

5. The process of claim 3 wherein the 16,3-bromo group is removed with Raney nickel.

6. The process of claim 4 wherein the 12-bromo group and 16fi-bromo group are removed with Raney nickel.

7. 5,6 dibromo 16a,17a-oxido-pregnan-3fl-ol-11,20- dione acetate.

8. 5,6,165 tribromo-pregnan-3 3,17a-diol-11,20-dione 3-acetate.

9. A compound selected from the class consisting of 5,6,16;8,21 tetrabromo pregnan-3B,17a-diol-11,20-dione and its 3-mono lower fatty acid esters.

10. 16,8 bromo-21-iodo-A -pregnen-3fl,17a-diol-11,20- dione.

11. 16a,17 x oxido-A -pregnen-3fi,21-diol-11,20dione 21-monoacetate.

12. 5,6 dibromo-l6a,17a-oxidopregnan-3fl,2l-diol-l 1, 20-di-one 21-acetate.

13. 5,6 dibromo-16a,17a-oxido-pregnan-21-o1-3,11,20- trione ZI-acetate.

14. *16a,17a oxido-A -pregnen-2J1-ol-3J1,20-trione-21- acetate.

15. A compound selected from the group consisting of 5,6,12,16fl,21 pentabromo-pregnan-3fi,17a-diol-11,20dione and its 3-mono lower fatty acid esters.

References Cited in the file of this patent UNITED STATES PATENTS 2,596,562 Kaufmann et a1 May 13, 1952 2,602,804 Kendall July 8, 1952 2,684,364 Jones July 20, 1954 2,752,339 Julian et a1. June 26, 1956 2,776,969 Rosenkranz et a1 Jan. 8, 1957 2,816,108 Julian et al Dec. 10, 1957 2,899,428 Rothman et al Aug. 11, 1959

Claims (1)

1. A PROCESS FOR THE PRODUCTION OF THE LOWER FATTY ACID ESTERS OF 16A,17A-OXIDO-$5-PREGNEN-3B-OL-11,20-DIONE COMPRISING SELECTIVELY ACYLATING 11A-HYDROXY-DISOGENIN IN AN INERT SOLVENT AT LOW TEMPERATURE TO FORM THE 3-LOWER FATTY ACID ESTERS THEREOF, OXIDIZING THE ESTERS WITH AN OXIDIZING AGENT TO FORM THE 3-LOWER FATTY ACID ESTERS OF 11-KETO-DIOSGENIN, OXIDATIVELY DEGRADING THE SIDE CHAIN OF THE LAST MENTIONED ESTERS TO FORM THE CORRESPONDING 3-LOWER FATTY ACID ESTERS OF $5,16-PREGNADIEN-3B-OL-11,20DIONE, EPOXIDIZING THE LAST MENTIONED COMPOUND WITH A PEROXIDIZING AGENT TO FORM 16A,17A-OXIDO-$5-PREGNEN-3BOL-11,20-DIONE AND ESTERIFYING THIS LAST MENTIONED COMPOUND WITH A LOWER FATTY ACID ANHYDRIDE. 7. 5,6-DIBROMO-16A,17A-OXIDO-PREGNAN-3B-OL-11,20DIONE ACETATE.